1. Field of the Invention
The present invention relates to a novel thermoplastic, biodegradable multi-block hydrogel copolymer used for drug delivery matrix, having both hydrophobic blocks and hydrophilic blocks. More specifically, this invention concerns a thermoplastic, biodegradable hydrogel copolymer which is easily degraded and excreted in the human body by the hydrolysis of intramolecular ester and amide bonds. The structure of present copolymer comprises i) a hydrophilic and swellable soft domain consisting of polyethyleneoxide (PEO), and ii) a hydrophobic, biodegradable, crystallizable and non-swellable hard domain consisting of polylactide (PLA), polyglycolide (PGA), polylactideglycolide (PLGA) and polycaprolactone (PCL).
2. Description of the Prior Art
Recently, drug delivery systems for regulating drug release to a specific site within the range of a constant effective dose has been researched very actively. For this purpose, biomedical polymers have been developed as a drug delivery matrix. However, biomedical polymers developed so far have some drawbacks as follows:
i) It is difficult to use biomedical polymers for delivering the drugs having a high molecular weight; PA1 ii) Physical treatment is required for removing non-biodegradable copolymers, if such non-biodegradable copolymers are used for a drug delivery matrix; and PA1 iii) In case of hydrogels developed up to now, these materials have very low processibility due to their crosslinked nature. Furthermore, these materials cannot be used easily as a drug delivery matrix due to their toxicity to the human body. PA1 i) the copolymers can be easily processed into appropriate preparations by simple processing methods, such as, infusion processing methods or solvent casting methods, since there is no chemical crosslinkage in the copolymers; and PA1 ii) the copolymers can be easily degraded into small and nontoxic molecules by simple hydrolysis or enzyme hydrolysis in order to be easily excreted through the kidney. PA1 B( - - - ) represents a hydrophobic, biodegradable, crystallizable, and non-swellable polymers essentially consisting of polylactide(PLA), polyglycolide (PGA), a copolymer of PLA/PGA, polycaprolactone, polyorthoester and/or polyanhydride; PA1 X represents a biodegradable chemical linkage, such as an amide linkage, ester linkage, and/or carbonate linkage; PA1 Y represents a chemical linkage between block (A) and block (B), or block (B) and block (B), such as an amide linkage, ester linkage, and/or carbonate linkage; PA1 n represents an integer 0 to 10; PA1 q represents an integer 3 to 4.
To solve the above mentioned drawbacks, the inventors have researched thermoplastic, biodegradable hydrogel copolymers having the following properties:
Biodegradable copolymers disclosed until now are aliphatic polyester, polyorthoester, polyanhydride, poly .alpha.-amino acid, polyphosphagen, polyalkylcyanoacrylate. Among the aliphatic polyesters, polylactide (PLA), polyglycolide (PGA) and polylactideglycolide (PLGA) have been approved as copolymers nontoxic to humans by the FDA. These copolymers have been applied as drug delivery devices to carry the drugs having small molecular weight.
Recently, polypetides or proteins produced by cell engineering or recombinant DNA technology have been approved as major medicines. However, these medicines have been administered only by injection, because these medicines are water-soluble and are very unstable macromolecular compounds with a short half-life. Therefore, finding another suitable delivery route for these compounds becomes a major research subject.
The application of aliphatic polyesters as a delivery system for protein drugs has some handicaps owing to their difficulties in loading process, complicated release mechanism, low degradability and their hydrophobic properties. Therefore, the improved degradable materials have been required as a drug delivery matrix for protein drugs.
Block copolymers as a drug delivery matrix are disclosed by U.S. Pat. No. 4,942,035. These copolymers are block copolymers in the shape of PLA/PEO/PLA or PGA/PEO/PGA which comprise polyethyleneoxide as a hydrophilic block and polylactide (D-, L- or DL-form), polyglycolide, poly-.epsilon.-caprolactone or poly-3-hydroxybutylic acid as a hydrophobic block. However, these block copolymers have some drawbacks, for example, they are difficult to excrete from the human body, because they use too high molecular weight PEO.
On the other hand, diblock and triblock copolymers having polyalkyleneoxide, polyglycolide and trimethylene carbonate are disclosed by U.S. Pat. No. 4,716,203. These block copolymers were invented for coating materials, and contain some materials which are not easily degraded and toxic to human body.
Other block copolymers having polyethylene glycol as a hydrophilic component and polylactide as a hydrophobic component are reported in J. Pol. Sci. (A): Vol. 27,2151(1989), J. Pol. Sci. (A): Vol. 39,1(1990), J. Applied. Poly. Sci.: Vol. 50, 1391 (1993) and J. Applied. Poly. Sci.: Vol. 51,473 (1994). However, these copolymers were prepared by simple copolymerization of the two components to be used as drug delivery matrix.